Compositions and Methods for use of CXCL12 in Treatment of Bone Disorders

Abstract

The present invention provides compositions and methods for treating a disease or disorder associated with bone defects or reduced or abnormal bone formation.

What is claimed is: 
     
         1 . A method of treating a disease or disorder associated with bone defects or reduced or abnormal bone formation in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising a modulator of CXCL12. 
     
     
         2 . The method of  claim 1 , wherein the modulator of CXCL12 is at least one of the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, an antisense nucleic acid molecule. 
     
     
         3 . The method of  claim 2 , wherein the modulator of CXCL12 is a protein and the protein comprises at least one sequence of SEQ ID NOs:1-4. 
     
     
         4 . The method of  claim 1 , wherein the modulator of CXCL12 is a fusion molecule, wherein the fusion molecule comprises (a) CXCL12 or a fragment of CXCL12 and (b) a bisphosphonate. 
     
     
         5 . The method of  claim 3 , wherein the fusion molecule comprises a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 15, and SEQ ID NO: 16. 
     
     
         6 . The method of  claim 4 , wherein the bisphosphonate comprises a structure of formula (1): 
       
         
           
           
               
               
           
         
         wherein R 11  and R 12  are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, cycloalkyl, heterocyclyl, OR 13  and —(CH 2 ) n —NR 13 R 14 ; 
         each occurrence of R 13  and R 14  is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, cycloalkyl, and heterocycle; and 
         n is an integer from 0 to 10. 
       
     
     
         7 . The method of  claim 6 , wherein in formula (1), R 11  and R 12  are each independently selected from the group consisting of hydrogen, —OH, methyl, Cl, —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —(CH 2 ) 5 —NH 2 , —(CH 2 ) 2 —N(CH 3 )((CH 2 ) 4 CH 3 ), 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 6 , wherein the bisphosphonate is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a salt thereof. 
     
     
         9 . The method of  claim 1 , wherein the disease or disorder is selected from the group consisting of osteoporosis, idiopathic primary osteoporosis, age-related osteoporosis, glucocorticoid-induced osteoporosis, Haj du-Cheney syndrome, osteolysis, post-transplant bone disease, Paget's disease of bone, bone fracture, periodontal disease, and periodontitis. 
     
     
         10 . A fusion molecule, wherein the fusion molecule comprises (a) CXCL12 or a fragment of CXCL12 and (b) a bisphosphonate. 
     
     
         11 . The fusion molecule of  claim 10 , wherein the fusion molecule comprises a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 15, and SEQ ID NO: 16. 
     
     
         12 . The fusion molecule of  claim 10 , wherein the bisphosphonate comprises a structure of formula (1): 
       
         
           
           
               
               
           
         
         wherein R 11  and R 12  are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, cycloalkyl, heterocyclyl, OR 13  and —(CH 2 ) n —NR 13 R 14 ; 
         each occurrence of R 13  and R 14  is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, cycloalkyl, and heterocycle; and 
         n is an integer from 0 to 10. 
       
     
     
         13 . The fusion molecule of  claim 12 , wherein in formula (1), R 11  and R 12  are each independently selected from the group consisting of hydrogen, —OH, methyl, Cl, —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —(CH 2 ) 5 —NH 2 , —(CH 2 ) 2 —N(CH 3 )((CH 2 ) 4 CH 3 ), 
       
         
           
           
               
               
           
         
       
     
     
         14 . The fusion molecule of  claim 12 , wherein the bisphosphonate is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a salt thereof. 
     
     
         15 . A method of fusing a CXCL12 or a fragment of CXCL12 to a bisphosphonate, the method comprising:
 (a) reacting the N-terminal amine of the CXCL12 or N-terminal amine of the fragment of CXCL12 with 4-ethynylbenzaldehyde to form an alkynyl terminated CXCL12, or incorporating an azidohomoalanine amino acid at the C-terminus of the CXCL12 or the C-terminus of the fragment of CXCL12 to form an alkynyl terminated CXCL12; and   (b) conjugating the alkynyl terminated CXCL12 to an azido-bisphosphonate by azide-alkyne cycloaddition, wherein the conjugation of the alkynyl terminated CXCL12 to the azido-bisphosphonate fuses the CXCL12 or the fragment of CXCL12 to the bisphosphonate.